Abstract Abdominal aortic aneurysms (AAA) are responsible for 10,000 documented deaths every year in the US. While most aneurysms are asymptomatic, highly lethal complications, rupture and dissection do occur in a subset of patients. Aneurysm diameter is the best-known predictor of its propensity to rupture, and accordingly, aneurysm repair is recommended for large, or symptomatic AAA. However, many ruptures occur in smaller aneurysms that do not meet the criteria for repair; and conversely, some larger aneurysms do not rupture. AAA treatment remains limited to surgical or endovascular repair, as several promising medical therapies have failed in clinical studies. As such, novel tools (e.g., molecular imaging) are needed to better risk stratify patients, develop effective medical therapies, and monitor therapeutic effectiveness. Matrix metalloproteinases (MMP) activation promotes vascular remodeling in AAA, in part through degradation of elastin and other matrix proteins. Our previous studies have established the feasibility of MMP-targeted imaging to detect vascular remodeling by micro single photon emission computed tomography (SPECT)/CT in murine models of aneurysm. However, a number of limitations of the SPECT tracer and technology precluded clinical translation for vascular imaging. To address these limitations, we developed a novel family of MMP- targeted tracers (RYM) with improved pharmacokinetics, including a first in the class positron emission tomography (PET) tracer, 64Cu-RYM2. Here, we seek to further develop, evaluate, and clinically translate 64Cu-RYM2 for first in human imaging studies in AAA, hypothesizing that MMP PET/CT imaging with 64Cu- RYM2 can detect AAA MMP activity. Our specific aims are to evaluate 64Cu-RYM2 binding to human AAA tissue; address 64Cu-RYM2 pharmacokinetics and imaging performance in murine AAA in relation to tissue MMP activity; and translate 64Cu-RYM2 for human AAA imaging. Leveraging the resources and complementary expertise of the PIs and co-investigators at Yale School of Medicine and Washington University, including an NIBIB-funded P41- center at Washington University, these studies will establish the potential of 64Cu-RYM2 to quantify MMP activation in human AAA, and set the stage for a multi-center trial of MMP PET/CT imaging for AAA risk stratification.